SOHO Italy 2025 | Toxicities associated with BCMA, GPRC5D & FcRH5-targeting bispecifics and advice on their management

So, BCMA is the most ubiquitous one. At the time of this recording, there are two FDA-approved bispecifics that target BCMA and two FDA-approved CAR-Ts. There’s going to be a third FDA-approved bispecific likely within the next few months by the name of linvoseltamab. Now BCMA in the realm of T-cell redirection, the main toxicity is infections because patients will get significant hypogammaglobulinemia from them. And one of the things that we’ve learned is primary prophylaxis with IVIG is critical, meaning we don’t wait for the IgG to drop really low and we don’t wait for infections, we just start it. Because we and other groups have shown that if you start primary prophylaxis with IVIG, you can have a resultant tenfold reduction in grade three to five infections with this approach. So, that’s really the main thing is preventing infections with BCMA. 

For GPRC5D, there’s three big ones. GPRC5D has other expression beyond just the plasma cells, and although the infectious risk is less than BCMA, it’s not zero. But GPRC5D is also expressed on the squamous epithelium of the hands and feet, so you can get a desquamating rash, which to me looks very much like the zoster rash. So using emollients can really help there. It’s expressed on the oropharynx and the salivary glands. So dysgeusia, dry mouth, xerostomia are a concern. So really making sure nutrition is consulted, Biotene and artificial saliva may be helpful. Additionally, we found recently that there is GPRC5D expression in the cerebellum. So ataxia and dysdiadochokinesia can be seen. So being careful to clearly tease out what is lightheadedness versus vertigo versus ataxia in the patients, it can be really difficult to know what’s other toxicity or what’s GPRC5D-related toxicity. 

FCRH5 doesn’t have the hand, foot, dysgeusia, or dysdiadochokinesia that GPRC5D does. It has less infection than BCMA, but probably more than GPRC5D. There have been a handful of cases of HLH with FCRH5. So really making sure we follow patients, you know, what their ferritin is doing throughout their initial therapy, what their blood counts, what their liver function is doing, because early detection and intervention of HLH is key. Although again, this is a very infrequent event with HLH, and we have seen this with other T-cell engaging assets like BCMA and GPRC5D. So it’s not unique with FCRH5, but it can be seen. But those are really the main toxicities to look out for.

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